Compositions of perphenazine and protriptyline for treating mental disorders



United. States Patent 3,478,151 COMPOSITIONS OF PERPHENAZINE AND PROTRIPTYLINE FOR TREATING MEN- TAL DISORDERS Carl Edward Nelson, Doylestown, Pa., assignor to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Filed Oct. 23, 1967, Ser. No. 677,084 Int. Cl. A0111 27/00 U.S. Cl. 424-247 4 Claims ABSTRACT OF THE DISCLOSURE A pharmaceutical composition for the treatment of mental disorders consists of protriptyline and perphenazine. The protriptyline offsets the extrapyramidal side reactions of the perphenazine.

This invention relates to pharmaceutical compositions, and more particularly, it relates to novel therapeutic compositions useful in the treatment of mental disorders which are accompanied by a marked depressive mood.

These mentally depressed disorders are now recognized as among the most distressing of human diseases. The person suffering from one of many recognized mentally depressed abnormalities presents a serious problem to his associates and family and is often unable to carry on a self sustaining existence. The disorder may range from a more or less incapacitating depression to a total personality disintegrating condition such as schizophrenia.

Physicians now have available a number of drugs which alleviate these mentally depressed disorders so that the person is able to carry on a more satisfying life but many of the drugs cause side reactions which are disturbing or at least annoying to the patient. One of the most useful drugs is perphenazine. Although it is extraordinarily useful as a tranquilizer it unfortunately induces extrapyramidal reactions in a fair percentage of the patients. These extrapyramidal reactions include akanesia, dyskinesia, akathisia and parkinsonism.

The present invention provides a pharmaceutical composition which secures the tranquilizing benefits or perphenazine with minimal or complete absence of these extrapyramidal reactions. The tendency toward parkinsonism, in particular, is antagonized. These advantages are obtained by combining with the perphenazine the mental health agent protriptyline so that they are conjointly administered to the patient.

This combination of drugs is of greater benefit to a mentally distressed person than is either drug alone. For example, if a sufficiently large dose of perphenazine alone is given to a patient to obtain the desired sedation, the extrapyramidal side effects which emerge may require an undesirable reduction in the perphenazine dose. The physician then is presented with the dilemma of choosing between an adequate tranquilizing dose and its attendant side effects or a small and inadequate dose of the perphenazine. With the combination of this invention an adequate total dose of perphenazine can be administered so that the desired alleviation of the mental condition is obtained, without evoking extrapyramidal reactions. The protriptyline component, in addition to contributing its own beneficial psychiatric activity, serves in particular to reduce or overcome the parkinson-like syndrome which Would emerge due to the perphenazine component. In this respect the protriptyline seemingly exerts an anticholinergic effect which offsets the parkinson-like syndrome.

Moreover, patients who can tolerate the usual higher doses of perphenazine and protriptyline and who are not relieved by a higher dose of either drug alone, are relieved 3,478,151 Patented Nov. 11, 1969 by their conjoint administration. Thus, if a mentally depressed person does not obtain satisfactory relief from the use of 4 mg. of perphenazine and can tolerate this dosage, protriptyline can be administered conjointly therewith and obtain an antidepressive effect that could not be obtained with either a large amount of perphenazine or with protriptyline alone. In this respect the perphenazine and protriptyline exerts a synergistic effect upon each other to produce a result which could not be achieved with either drug by itself.

Protriptyline is the generic name for the chemical compound N -methyl-5H-dibenzo[a,d]cycloheptadiene-5 propylamine sold as its hydrochloride under the trademark Vivactil by Merck and Co., Inc. It can be manufactured by the process disclosed in South Africa Patent 3,486.

Perphenazine, chemically is 2-chloro-10-{3-[1-(2-hydroxyethyl)-4-piperazinyl]propyl} phenothiazine and it is sold under the trademark Trilafon, by Schering Co. It is included in United States Patent 2,838,507.

Compositions of the invention would be made up so that a unit dosage would contain from 5 to 10 mg. of protriptyline and from 1 to 4 mg. of perphenazine. A preferred formulation would contain 5 to 10 mg. of protriptyline and 2 mg. of perphenazine. One or two of these tablets would be taken three or four times daily. These formulations would be made up so that one or two capsules or tablets administer these amounts of the two therapeutic agents or so that one or two tablespoonsful of a liquid suspension or elixir administer these amounts. A mixture of the proper amounts of the two essential ingredients could be placed on the tongue and be carried into the stomach by swallowing water but it is best that a conventional pharmaceutical carrier such as a capsule, a tablet, or a liquid suspension be used.

The examples which follow will serve to further illustrate the invention:

Ten gms. of protriptyline, 2 gms. of perphenazine, gms. lactose and 17 gms. of starch are mixed together. The blended powders are passed through a 40-mesh stainless steel screen to insure unifority. The mix then is wet granulated with 40 gms. of a 10% starch paste in water, and sufficient water is added to make a suitable mass. The wetted materials are screened through a No. 12 stainless steel screen, dried overnight at 40 C., and the dried granules are sent through a No. 14 mesh screen. Thereafter, 2 gms. of magnesium stearate is added, blended and compressed into standard curvature tablets, each weighing 200 mg. The tablets are sized with a protective coat of pharmaceutical glaze and sugar-coated in conventional manner.

EXAMPLE 11 Following the procedure described in detail above but using 1 mg. of perphenazine instead of 2 mg. per tablet a different dosage ratio is produced.

EXAMPLE III Following the procedure described in detail above but using 4 mg. of perphenazine instead of 2 mg. per tablet a different dosage ratio is produced.

EXAMPLE IV A tablet is made up by following the above procedure, so that it contains 4 mg. of perphenazine and 5 mg. of proptriptyline.

The pharmaceutical preparation of this invention is useful for the treatment of (1) acute and chronic states With associated depressed mood, (2) patients with depression in whom anxiety and/or agitation are severe, and (3) patients With severe anxiety and/or agitation and depressed mood in Whom symptoms must be controlled While more definitive diagnostic measures are being undertaken. In many of these patients, anxiety masks the depressive state so that, although therapy With a tranquilizer appears to be indicated, the administration of a tranquilizer alone will not be adequate.

Suicidal patients commonly present a mixture of anxiety and depression. When there is danger of suicide, this drug combination may represent more effective therapy than the administration of either of its components alone. Schizophrenic patients of all diagnostic categories Who have associated depressive symptoms should be considered for therapy with this drug combination. It can be expected that when this preparation is used less electroshock therapy will be required in the treatment of schizophrenic patients With severe anxiety and depression. In some instances, the need for electroshock therapy can be eliminated.

As the protriptyline component does not have a tranquilizing activity it has the double advantage that it contributes is own beneficial antidepressant efiFect and in addition serves as an anticholinergic agent to antagonize the extrapyramidal side effects of the perphenazine.

What is claimed is:

References Cited A. St. Jean et al., Current Therapeutic Research, vol. 8, No. 10 (October 1966), pp. 483-486.

Gordon, Psychopharmacological Agents II, p. 294 (1967).

Gordon, (1964).

Kennedy et al., Am. J. of Psychiatry, vol. 118, No. 6, December 1961, pp. 547-548.

Dorfman, Am. J. of Psychiatry, vol. 120, No. 3, September 1963, pp. 275276.

Psychopharmacological Agents I, p. 42

ALBERT T. MEYERS, Primary Examiner S. J. FRIEDMAN, Assitsant Examiner U.S. Cl. X.R. 424-330 

